Secondary metabolites are organic compounds that are not directly involved in the normal growth, development or reproduction of organisms. They are often used as defenses against predators, parasites and diseases, for interspecies competition, and to facilitate the reproductive processes (coloring agents, attractive smells, etc).
Secondary metabolites of fungi include both “friends and foes” of human health. For example, penicillin and derivatives produced by Aspergillus, Cephalosporium and Penicillium species are widely used antibiotics, lovastatin is a potent cholesterol-lowering drug produced by Aspergillus terreus and aflatoxins, produced by several Aspergillus species, are highly toxic carcinogens contaminating many crops.
Secondary metabolic pathways are often tightly correlated with the fungal developmental program and response to external cues including light. Since secondary metabolites are usually restricted to a much more limited group of organisms, they have long been of prime importance in taxonomic research. Secondary metabolites are especially useful for drug or other technological development, or as an inspiration for unnatural products. Biosynthetic genes for fungal secondary metabolites are often clustered and regulated by pathway-specific transcription factors. Secondary metabolism is also regulated at an upper hierarchic level by a global epigenetic control mechanism. However, methods of producing large amounts of secondary metabolites are difficult and provide unpredictable results. Therefore a need exists for methods of producing large amounts of secondary metabolites that address these problems.
The distribution of natural products is characteristically restricted to certain fungal taxa, particularly the Ascomycetes. Perhaps the greatest number of known secondary metabolites has been ascribed to the Ascomycete genus Emericella (asexual stage=Aspergillus). Much of the current understanding of fungal secondary metabolite regulation arises from studies of the genetic model Aspergillus nidulans. This organism produces many natural products including sterigmatocystin ST (ST; the penultimate precursor to aflatoxin) and penicillin and has been used as a heterologous host to study the biosynthesis of other natural products including lovastatin. Critical advances in understanding fungal secondary metabolism have been largely based on primary studies from A. nidulans and/or secondary studies in other fungi where researchers were able to exploit the knowledge gained from A. nidulans to their fungus of choice.
A. nidulans, a mold, produces many compounds relevant to biotechnology and human health and is a well-suited model for the analysis of the interplay between secondary metabolism, light and differentiation. A. nidulans grows vegetatively in the soil by hyphal tip extension until competent for development and secondary metabolism. In reproduction, A. nidulans forms airborne asexual spores in light but preferentially undergoes sexual reproduction in the dark. Sexual reproduction in the dark results in an increase in secondary metabolism and in the formation of sexual fruit bodies called cleistothecia, which consist of different cell types. Mutations resulting in defects in fungal development often impair secondary metabolism. There is genetic evidence for a connection between fruitbody formation, secondary metabolism, and light in A. nidulans reproduction, but the molecular mechanism is not known.
Aspergillus flavus, an opportunistic pathogen of oil seeds, occurs as a saprophyte in soils worldwide and colonizes several important agricultural crops, such as maize, peanut, and cottonseed, before and after harvest. The pathogen generates asexual spores, conidia, as the source of inoculum and overwinters as sclerotia which germinate to produce conidia in the subsequent season. A. flavus and other aspergilli, such as Aspergillus parasiticus, can produce the polyketide-derived carcinogenic secondary metabolite aflatoxin. In the United States, annual yield losses in the million-dollar range from aflatoxin contamination on peanut and maize crops are frequently reported. Aflatoxin-contaminated food and feed is also a major problem in developing countries, especially in Asia and Africa. Recently, an outbreak of aflatoxin poisoning from maize was reported to have killed a hundred people in Kenya. Therefore, measures to control Aspergillus infections and aflatoxin production are urgently needed to protect human and animal health. The identification and characterization of molecules necessary for A. flavus conidial, sclerotial, and aflatoxin production are critical to develop rational control strategies.
VeA, a conserved velvet protein encoded by the veA gene, increases expression during sexual development. However, VeA transport into the nucleus is inhibited by light. It acts as a negative regulator of asexual development. VeA is required for cleistothecial production in A. nidulans and sclerotial production in both A. parasiticus and A. flavus. In addition, the VeA gene regulates the expression of sterigmatocystin (a precursor of aflatoxin) and penicillin genes in A. nidulans and aflatoxin genes in A. parasiticus and A. flavus. VeA interacts with LaeA in an as-yet-unclear mechanism, althouth analysis shows that VeA and LaeA negatively regulate each other at the transcript level in A. nidulans (1) and LaeA negatively regulates veA in A. flavus (21).
LaeA, another protein located in the cell nucleus, is present in numerous fungi and is a master regulator of secondary metabolism in Aspergilli and other fungal genera. LaeA is also necessary for sclerotial formation in A. flavus and affects cleistothecial development in A. nidulans. 
The deletion of LaeA silences numerous secondary metabolite gene clusters, including those responsible for the syntheses of the antibiotic penicillin as well as for toxins such as ST or gliotoxin. It has been suggested that LaeA might control the accessibility of binding factors to chromatin regions of secondary metabolite clusters because LaeA prevents heterochromatin maintenance of some clusters.
Other factors have been reported which link morphological development with secondary metabolism. Of particular interest are a family of oxylipin-producing oxygenases (encoded by ppo and lox genes) which have been shown to balance ascospore and conidial production in A. nidulans (40, 41) and sclerotial and conidial production in A. flavus, as well as secondary metabolite production in both species. Most recently, a density-dependent switch from sclerotial-to-conidial development in A. flavus was found to be affected by oxylipin production. Both oxylipin production and the response to oxylipin signaling are dependent on an intact VeA protein. VeA is also required for ppoA expression, and VeAPpoA interactions affect both sexual and asexual development in A. nidulans. The impact of the loss of these proteins on pathogenesis has been explored to some degree for LaeA and Ppo mutants but not yet reported for VeA. LaeA is a key determinant in aspergillosis caused by A. fumigatus and seed rot by A. flavus and Ppo loss impacts virulence attributes of A. fumigatus, A. nidulans, and A. flavus. 
Despite present methodologies, a need exists for improved methods of controlling production of secondary metabolites to obtain improved production of important natural products and/or novel natural products with medicinal value.